Project Summary: Destabilization of the genome is known to cause and perpetuate many diseases, particularly cancer. Normally, genome stability is maintained by numerous cellular processes devoted to preserving and repairing DNA. As a result, cells rarely acquire new mutations. However, recent findings from our group and others have demonstrated that cells can undergo transient episodes of genome destabilization and acquire numerous genomic mutations simultaneously. These events, termed saltational bursts of genomic instability, drive rapid genome evolution and are posited to contribute to the initiation and progression of multiple types of cancer. Currently, we understand very little about the properties and causes of saltational bursts, largely because a model system with which to rigorously study these events has been lacking. We have recently characterized bursts of genomic instability in the budding yeast Saccharomyces cerevisiae. Based on compelling preliminary data, we hypothesize that stochastic failures in genome maintenance can cause saltational bursts of genomic instability and lead to transient mutagenic episodes. In this application, I propose to use innovative genomic and cellular approaches to comprehensively explore key attributes of saltational bursts of mutagenesis. Specifically, I will 1) investigate the temporal properties of bursts in order to define the duration of these destabilizing episodes, 2) determine whether bursts occur through defects in specific genome integrity pathways, and 3) determine how variable activity of these pathways modulates the frequency and mutational load of saltational bursts. By conducting the above studies, I will contribute much needed insight into the mutational mechanisms that drive rapid evolution. Moreover, these studies will strengthen our understanding of the mutagenic events that give rise to diseases.